serval:BIB_1F376E063F34
ASC filament formation serves as a signal amplification mechanism for inflammasomes.
10.1038/ncomms11929
000379083600001
27329339
Dick
M.S.
author
Sborgi
L.
author
Rühl
S.
author
Hiller
S.
author
Broz
P.
author
article
2016
Nature Communications
2041-1723
2041-1723
journal
7
11929
A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASC(PYD) into filaments and cross-linking of these filaments by ASC(CARD). ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASC(PYD) is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production.
eng
60_published
true
peer-reviewed
University of Lausanne
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